Poly (vinyl alcohol) hydrogel

ABSTRACT

The present invention comprises a poly (vinyl alcohol) hydrogel construct having a wide range of mechanical strengths for use as a human tissue replacement. The hydrogel construct may comprise a tissue scaffolding, a low bearing surface within a joint, or any other structure which is suitable for supporting the growth of tissue.

RELATED APPLICATIONS

[0001] This application claims a continuation priority to applicationSer. No. 09/271,032 filed on Mar. 17, 1999, which issued as U.S. Pat.No. ________________ on ________________ and which in turn claimspriority to application Ser. No. 08/932,029, filed on Sep. 17, 1997which issued as U.S. Pat. No. 5,981,826 on Nov. 9, 1999, and whichclaims priority to provisional application Ser. No. 60/045,875, filed onMay 5, 1997, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates generally to hydrogel materials.More specifically, the present invention relates to a poly(vinylalcohol) (“PVA”) hydrogel.

DESCRIPTION OF THE PRIOR ART

[0003] Most tissues of the living body include a large weight percentageof water. Therefore, in a selection of a prosthesis, a hydrous polymer(hydrogel) is considered to be superior in biocompatibility as comparedto nonhydrous polymers. Although hydrogels do less damage to tissuesthan nonhydrous polymers, conventional hydrogels have historicallyincluded a serious defect in that they are inferior in mechanicalstrength. For that reason, the use of hydrogels has been extremelylimited in the past.

[0004] Artisans have proposed a number of hardening means for improvingmechanical strength. Some hardening means include treating the hydrogelwith a cross-linking agent such as formaldehyde, ethylaldehyde,glutaraldehyde, terephthalaldehyde or hexamethylenediamine.Unfortunately, however, it is well known that those treatments decreasethe biocompatibility of the hydrogel biomaterial. One example of apopular hydrogel which has been proposed for use as a biomaterial isPVA.

[0005] Numerous references generally describe the process of freezingand thawing PVA to create a hydrogel: Chu et al., Poly(vinyl alcohol)Cryogel: An Ideal Phantom Material for MR Studies of ArterialElasticity, Magnetic Resonance in Medicine, v. 37, pp. 314-319 (1997);Stauffer et al., Poly (vinyl alcohol) hydrogels prepared byfreezing-thawing cyclic processing, Polymer, v.33, pp. 3932-3936 (1992);Lozinsky et al., Study of Cryostructurization of polymer systems,Colloid & Polymer Science, v. 264, pp. 19-24 (1986); Watase andNishinari, Thermal and rheological properties of poly (vinyl alcohol)hydrogels prepared by repeated cycles of freezing and thawing, Makromol.Chem., v. 189, pp. 871-880 (1988). The disclosure from these referencesis hereby incorporated by reference.

[0006] Another such reference is U.S. Pat. No. 4,734,097, issued toTanabe et al. on Mar. 29, 1988 (“Tanabe”). Tanabe proposes the constructof a molded hydrogel obtained by pouring an aqueous solution containingnot less than 6% by weight of a polyvinyl alcohol which has a degree ofhydrolysis not less than 97 mole percent and an average polymerizationdegree of not less than 1,100 into a desired shape of a vessel or mold,freeze molding an aqueous solution in a temperature lower than minus 5°C., then partially dehydrating the resulting molded product withoutthawing it up to a percentage of dehydration not less than 5 weightpercent, and if required, immersing the partially hydrated molded partinto water to attain a water content thereof in the range of 45 to 95weight percent.

[0007] The disadvantage to Tanabe et al. is that it necessarily requiresa step of dehydration in preparing the PVA hydrogel. There are severaldisadvantages associated with the dehydration step. First, thedehydration step adds additional time and capital expense associatedwith machinery which must accomplish the dehydration step. Additionally,dehydration may denature bioagents included in the hydrogel.

[0008] Hyon et al., U.S. Pat. No. 4,663,358 is directed to producing PVAhydrogels having a high tensile strength and water content. However,this patent is not directed to hydrating the PVA with water alone, butrather uses a mixture of water and an organic solvent such as dimethylsulfoxide (DMSO). DMSO is recognized as an initiator of carcinogenicity.Residual amounts of organic solvents in the resultant PVA hydrogelrender such products undesirable for biomedical applications,particularly where the hydrogel is to be used for long term implantswithin the body.

[0009] Wood et al., U.S. Pat. No. 5,260,066 is directed to a cryogelbandage having a therapeutic agent. The modulus of elasticity propertiesof the product of Wood et al. are insufficient to provide a jointreplacement construct of the present invention.

[0010] With the foregoing disadvantages of the prior art in mind, it isan object of the present invention to provide a biocompatible PVAhydrogel which includes a mechanical strength range sufficient for awide variety of applications as biomaterial.

[0011] It is another object of the present invention to provide a methodfor producing the PVA hydrogel which precisely controls the mechanicalstrength thereof, and which eliminates any dehydration step prior toimplantation.

[0012] Other objects, features and advantages of the present inventionwill become apparent upon reading the following specification.

SUMMARY OF THE INVENTION

[0013] Generally speaking, the present invention relates to a novelpoly(vinyl alcohol) (“PVA”) hydrogel tissue replacement construct and aprocess for making the construct.

[0014] More specifically, the present invention relates to anon-dehydrated PVA hydrogel construct which is capable of being moldedinto a number of shapes, and which is capable of retaining a wide rangeof mechanical strengths for various applications.

[0015] The PVA hydrogel may comprise a PVA polymer starting material inthe form of a dry powder wherein the degree polymerization of the PVAmay range approximately 500 to 3,500. The tissue replacement inaccordance with the present invention may include approximately 2 toapproximately 40 parts by weight PVA and approximately 98 to 60 parts byweight water. Additionally, the hydrogel may include an isotonic salinesolution substitute for water to prevent osmotic imbalances between thetissue replacement and surrounding tissues. The replacement may alsoinclude a number of bioactive agents including, but not limited to,heparin, growth factors, collagen crosslinking inhibitors such asβ-aminopropeonitrile (βAPN), matrix inhibitors, antibodies, cytokines,integrins, thrombins, thrombin inhibitors, proteases, anticoagulants andglycosaminoglycans.

[0016] A process in accordance with the present invention involvesmixing water with the PVA crystal to obtain a non-dehydrated PVAhydrogel, thereby eliminating the dehydration step prior toimplantation. More specifically, the present invention involves freezingand thawing the PVA/water mixture to create an interlocking mesh betweenPVA polymer molecules to create the PVA hydrogel. The freezing andthawing step may be performed at least twice, with mechanical strengthof the PVA hydrogel increasing each time the freezing and thawing stepis performed. The process may include the further steps of pouring thePVA/water mixture into a mold, freezing the mixture, and the thawing themixture to obtain a non-dehydrated construct. Additionally, the processmay also include the step of removing the construct from the mold,immersing the construct in water, freezing the construct while immersedin water and thawing the construct while immersed in water to increasethe mechanical strength of the construct. The process may also includethe steps of adding bioactive agents to the hydrogel.

[0017] Because it can be manufactured to be mechanically strong, or topossess various levels of strength among other physical properties, itcan be adapted for use in many applications. The hydrogel also has ahigh water content which provides desirable properties in numerousapplications. For example, the hydrogel tissue replacement construct isespecially useful in surgical and other medical applications as anartificial material for replacing and reconstructing soft tissues inhumans and other mammals. Soft tissue body parts which can be replacedor reconstructed by the hydrogel include, but are not limited to,vascular grafts, heart valves, esophageal tissue, skin, corneal tissue,cartilage, meniscus, and tendon. Furthermore, the hydrogel may alsoserve as a cartilage replacement for anatomical structures including,but not limited to an ear or nose. The inventive hydrogel may also serveas a tissue expander. Additionally, the inventive hydrogel may besuitable for an implantable drug delivery device. In that application,the rate of drug delivery to tissue will depend upon hydrogel pore sizeand degree of intermolecular meshing resulting from the freeze/thawdevice. The rate of drug delivery increases with the number of pores anddecreases with an increasing degree of intermolecular meshing from anincreased number of freeze/thaw cycles. The inventive hydrogel mayconsist essentially of a PVA polymer and about 20% to about 95% water,by weight. The mechanical and thermal properties of PVA hydrogelconstructs, for biomedical applications in particular, are important tothe performance of the constructs, as are the hydrogel's swellingproperties and coefficient of friction. The structures produced by thenovel process of this invention have advantageous properties in each ofthese areas. The process of the present invention produces crystallitesin the PVA hydrogel polymer which leads to unique and enhancedmechanical properties, thermal behavior and increased fatigue strength.

[0018] The tensile properties of the PVA hydrogel of the presentinvention may be characterized by its deformation behavior. The freedomof motion of the PVA polymer of the present invention is retained at alocal level while the network structure produced by the process of thisinvention prevents large-scale movements or flow. Rubbery polymers tendto exhibit a lower modulus, or stiffness, and extensibilities which arehigh. Glassy and semi-crystalline polymers have higher moduli and lowerextensibilities. The tensile and compressive properties of the constructof the present invention are reflected by a modulus of elasticity ofbetween about 0.1 and about 20 megaPascals, thus producing a hydrogelhaving excellent strength and flexibility characteristics.

[0019] In the liquid or melt state, a non-crystalline polymer possessesenough thermal energy for long segments of each polymer to moverandomly, called Brownian motion. As the mixture cooled, the temperatureis eventually reached at which all long range segmental motion ceases.This temperature at which segmental motions ceases, which is a functionof both the polymer material and how it is processed, is called theglass transition temperature. Experimentally, this glass transitiontemperature is often defined by incrementally increasing the temperatureof the hydrogel until sequential reaction begins and energy is absorbed.The glass transition properties of the PVA hydrogel construct providedby the method of the present invention is greater than about 40 degreesCelsius.

[0020] An integral part of the physical behavior of PVA hydrogelconstructs here disclosed is their swelling behavior in water, becausethe process of this invention requires that the PVA be immersed in waterin order to yield the final, solvated network structure. Thethermodynamic swelling force is counter balanced by the retractive forceof the hydrogel structure and, in the process of this invention,constrained by the mold in which the hydrogel is placed. Theseretractive forces of the hydrogel are described by the Flory rubberelasticity theory and its variations. Equilibrium is reached, in waterand at a particular temperature, when the if thermodynamic swellingforce is equal to the retractive force. The swelling properties of thePVA hydrogel construct of this invention are such that the dimensions ofthe construct are increased by swelling by less than about 20%, andpreferably less than about 5%, when immersed in water. Alternatively,the shrinkage is correspondingly less than 20%, and preferably less thanabout 5%. When the PVA hydrogel of this invention is used inapplications such as biomedical applications, for example as a kneejoint resurfacing agent, low friction is desirable. The construct of thepresent invention has a coefficient of friction of less than about 0.1.For a general description of the physical properties of polymers andtheir properties see, Biomaterials Science an Introduction to Materialsin Medicine, Ratner, et al. (Academic Press 1996), pp. 52-53 and 62.

[0021] The hydrogel is especially suitable for vascular grafts and heartvalve replacements, because the hydrogel is thromboresistant, andbecause of the particular mechanical and physiological requirements ofvascular grafts when implanted into the body. The hydrogel may also beused for contact lenses, as a covering for wounds such as burns andabrasions, as a nerve bridge, as a ureteral stent, and in otherapplications wherein a mechanically strong material is preferred.Because of its low coefficient of friction, the hydrogel may also beused as a coating to reduce friction between surfaces, such as on acatheter.

[0022] Other objects, features and advantages of the present inventionwill become apparent upon reading the following specification, whentaken in conjunction with the accompanying examples.

[0023] Reference will now be made in detail to the description of theinvention. While the invention will be described in connection withspecific examples, there is no intent to limit it to the embodiment orembodiments disclosed therein. On the contrary, the intent is to coverall alternatives, modifications and equivalents included within thespirit and scope of the invention as defined by the appended claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] In a preferred embodiment, a process in accordance with thepresent invention produces the hydrogel in a two stage process. In thefirst stage a mixture of poly(vinyl alcohol) and water is placed in amold, and repeatedly frozen and thawed, in cycles, until a suitablehydrogel is obtained. In a second stage, the hydrogel is removed fromthe mold, placed in water, and undergoes at least one other freeze-thawcycle until desirable mechanical properties are achieved. In the firststage, a series of sequential steps is employed comprising: (i) mixingwater with poly(vinyl alcohol) to obtain a poly(vinyl alcohol)/watermixture; (ii) freezing the mixture; (iii) thawing the mixture; and (iv)repeating the freeze and thaw steps, as necessary, until a poly(vinylalcohol) hydrogel having the desired physical properties is obtained. Ifnecessary, the second stage may then be employed.

[0025] Poly(vinyl alcohol) useful for the invention is typicallyobtained as a dry powder or crystal, and can vary based upon severalfactors, including molecular weight, degree of polymerization, anddegree of saponification (or hydrolysis). The molecular weight of thepoly(vinyl alcohol) can vary, and can be chosen depending upon theparticular application envisioned for the hydrogel. Generally,increasing the molecular weight of the poly(vinyl alcohol) increases thetensile strength and tensile stiffness, and thereby improves theproperties of constructs such as vascular grafts, wherein increasedstrength is desirable. In other applications, such as a nerve bridge,lower molecular weight poly(vinyl alcohol) can be employed because lowertensile strength and lower tensile stiffness are desirable. Poly(vinylalcohol) having an average molecular weight of from about 11,000 to500,000 is preferred for practicing the invention. Poly(vinyl alcohol)having an average molecular weight of from about 85,000 to 186,000 iseven more preferred for practicing the invention, especially whenproducing vascular grafts, and poly(vinyl alcohol) having an averagemolecular weight of from about 124,000 to 186,000 is especiallypreferred.

[0026] The average degree of polymerization for preferred poly(vinylalcohol)s generally ranges from about 500 to 3500, and poly(vinylalcohol) having a degree of polymerization of from about 2700 to 3500 isespecially preferred. Preferred poly(vinyl alcohol) typically has adegree of saponification (or hydrolysis) in excess of 80%, morepreferred poly(vinyl alcohol) is saponified (or hydrolyzed) in excess ofabout 98%, and even more preferred poly(vinyl alcohol) is saponified (orhydrolyzed) in excess of 99%.

[0027] The water that is mixed with the poly(vinyl alcohol) preferablyundergoes deionization, reverse osmosis and ultra filtered to minimizethe potential for any contamination of the poly(vinyl alcohol). Themixture is preferably prepared by mixing from about 2 to about 40 partsby weight poly(vinyl alcohol) with about 98 to 60 parts by weight water.The concentration of the poly(vinyl alcohol) contributes to thestiffness of the hydrogel and can thus be chosen depending upon thestiffness of the material one desires to obtain. A more preferablemixture is obtained by mixing from about 10 to about 30 parts poly(vinylalcohol) with from about 70 to about 90 parts by weight water, and anespecially preferred mixture is obtained by mixing about 25 partspoly(vinyl alcohol) with about 75 parts by weight water. Isotonic saline(0. 9% weight to volume in water) or an isotonic buffered saline may besubstituted for water to prevent osmotic imbalances between the materialand surrounding tissues if the hydrogel is to be used as a soft tissuereplacement.

[0028] After the poly(vinyl alcohol) and water are mixed, it is oftennecessary to process the mixture to ensure that the poly(vinyl alcohol)is adequately solubilized. Suitable solubilization processes aregenerally known in the art and include, for example, heating themixture, altering the pH of the mixture, adding a solvent to themixture, subjecting the mixture to external pressure, or a combinationof these processes. A preferred method is to heat the mixture at atemperature of about 95° C.-120° C., for a period of time not less than15 minutes and the one way of doing this, is an autoclave which alsoallows us to sterilize the mixture before further processing.

[0029] After the mixture has been prepared, air bubbles that may havebecome entrapped in the mixture should be removed. The solution can beallowed to sit for a period of time, preferably at an elevatedtemperature, to allow the air bubbles to rise out of solution. Themixture can also be placed in a sterile vacuum chamber for a short timeto bring the bubbles out of solution. The mixture can also becentrifuged at an elevated temperature to bring the bubbles out ofsolution.

[0030] Once prepared, the mixture can be poured into one or morepre-sterilized molds. If needed, the solution in the mold can be allowedto sit upright, or subjected to a vacuum in a vacuum chamber, to removeundesirable air bubbles. The shape and size of the mold may be selectedto obtain a hydrogel of any desired size and shape. Vascular grafts, forexample, can be produced by pouring the poly(vinyl alcohol)/watermixture into an annular mold. The size and dimensions of the mold can beselected based upon the location for the graft in the body, which can bematched to physiological conditions using normal tables incorporatinglimb girth, activity level, and history of ischemia. Suitable annularmolds for producing vascular grafts would include Y-shaped molds, whichcan be used to produce grafts having vascular branching. The hydrogelcan also be processed by cutting or otherwise forming the hydrogel intothe desired form after it has been produced. Although not necessary,molds are preferably capped or sealed to prevent dehydration and topreserve sterility. Typically, the mold is not filled entirely with thesolution in order to accommodate for the expansion of the hydrogelduring freezing.

[0031] Molds for practicing the invention can be comprised of manysuitable materials that will not react with the poly(vinyl alcohol)solution, that will maintain integrity over the required temperaturerange, and that will allow the hydrogel to be removed without damagingthe hydrogel. Suitable materials include but are not limited to naturaland synthetic resins, natural and synthetic polymers (including thosebased upon polycarbonates, acrylates and methacrylates, and poly(vinylalcohol)), glass, steel, aluminum, brass, and copper, among othermaterials. Outer molds that are compliant and elastic result in a morecomplete gelling and better physical properties than molds that arestiff. High pressure in the frozen poly(vinyl alcohol) reduces thestiffness of the resulting gel, and compliant molds reduce the pressureon the poly(vinyl alcohol) while it is frozen. Preferred annular moldsare constructed from smooth stainless steel or poly(vinyl chloride)tubes around stainless steel mandrels. More preferred annular

[0032] molds are constructed of compliant poly(vinyl chloride) or otherplastic tubes around stainless steel mandrels.

[0033] After the mixture has been poured into the mold, and the mold hasbeen sealed, it is frozen to a temperature preferably below about −5°C., and more preferably below about −20° C. The mixture shouldpreferably be frozen for at least 1 hour, including freezing time, morepreferably at least 4 hours, and most preferably from about 4 to about16 hours. In contrast to methods cited in the prior art, no dehydrationstep is required, and in a preferred embodiment dehydration is notemployed because of the importance of hydration to the final product.

[0034] After the mixture has been frozen, the temperature of the mixtureis raised and the mixture thawed. It is generally preferable to raisethe temperature to from about 5 to about 35° C., and to thaw thesolution at such temperature for a period of time of about 1 hour ormore, and more preferably at least 4 hours, and most preferably fromabout 4 to about 16 hours, including thawing time and time at suchtemperature. It is especially preferable to raise the temperature toabout 25° C., and to thaw the mixture at such temperature for about 12hours. Because the hydrogel is solubilized at higher temperatures, thetemperature of the mixture should not generally be raised above about45° C.

[0035] After the mixture has been frozen and thawed once under theforegoing conditions, the process may be repeated, although the exactprocess conditions need not be repeated for each freeze/thaw cycle.Generally, increasing the number of freeze/thaw cycles increases thetensile strength and tensile stiffness of the hydrogel, and can beimplemented for applications such as vascular grafts wherein higherstrength and stiffness are desired. In other applications, such as anerve tube, lower numbers of freeze/thaw cycles can be employed becauselower tensile strength and lower tensile stiffness are desirable. It isgenerally preferred to repeat the freeze/thaw cycle from about 0 toabout 15 times, and, in vascular graft applications especially, morepreferably from about 3 to about 6 times. Most preferably, thefreeze/thaw cycle is repeated twice, for a total of three freeze/thawcycles in the first stage.

[0036] After the material has undergone the first stage of freeze/thawtreatment it is carefully removed from the mold in order to avoiddamaging the material and immediately submerged in a liquid bath,preferably of deionized, sterile water. The material can be removed fromthe mold in either thawed or frozen state. Moreover, the material can beremoved from either part or the entire mold. For example, it may besuitable to retain the mandrels within the material if an annular moldis employed, to prevent the material from deforming. The bath should belarge enough so that the material is immersed completely in water, andcan be open or closed, but preferably closed to maintain sterility.

[0037] The second stage involves further freeze/thaw treatment of themolded material. After the mixture is immersed in water, it is againsubjected to one or more freeze/thaw cycles in the second stage of theprocessing. Again, the conditions for each freeze/thaw cycle in thesecond stage need not be identical. The mixture should preferably befrozen and thawed from about 1 to about 15 times, more preferably,especially for vascular graft applications, from 1 to 5 times, and mostpreferably 4 times, while the mixture is submerged in the water. As inthe first stage, increasing the number of freeze/thaw cycles increasesthe tensile strength and tensile stiffness, and the number of cycles canthus be selected based upon the particular application that is plannedfor the hydrogel.

[0038] The conditions under which the freeze/thaw cycles of the secondstage are carried out are generally comparable to the conditionsobserved in carrying out the first stage. After the mixture hasundergone the second stage of freeze/thaw cycles, it is ready for use.

[0039] The poly(vinyl alcohol) hydrogel of the present invention canalso comprise a 1.0 bioactive agent to lend to the hydrogel suitablephysiological properties for it to be used as a soft tissue replacement.The bioactive agent can be chosen based upon the particular applicationplanned for the replacement, and the particular physiological propertiesrequired of the replacement in the application involved. Many suchbioactive agents would be released gradually from the hydrogel afterimplantation, and thereby delivered in vivo at a controlled, gradualrate. The hydrogel can thus act as a drug delivery vehicle. Otherbioactive agents can be incorporated in to the hydrogel in order tosupport cellular growth and proliferation on the surface of thematerial. Bioactive agents which can be included in the replacementinclude, for example, growth factors, collagen crosslinking inhibitorssuch as β-aminopropeonitrile (βAPN) or cis-4-hydroxyproline, matrixinhibitors, antibodies, cytokines, integrins, thrombins, thrombininhibitors, proteases, anticoagulants, and glycosaminoglycans. Heparinsare particularly suitable agents for incorporating into vascular grafts,because of their anticoagulant properties, and thus their ability toinhibit thrombosis on the surface of the hydrogel.

[0040] In order to embed heparin or other bioactive agents into thehydrogel of the present invention any of a pre-sterilized heparinpowder, aqueous heparin or aqueous heparin suspension can be mixed intothe starting sterile poly(vinyl alcohol)/water mixture. After theheparin or other bioactive agent is incorporated into the poly(vinylalcohol)/water mixture, it is thermally processed along with thepoly(vinyl alcohol)/water mixture according to the process describedherein. Heparin and other bioactive agents can also be introduced intothe hydrogel by placing the hydrogel into a bath containing an aqueoussolution of the agent and allowing the agent to diffuse into thehydrogel.

[0041] The concentration of the heparin or other bioactive agent in themixture may be selected for the particular application involved. Forheparin incorporation into a vascular graft, concentrations willtypically range from 1 unit/ml. to 1,000,000 units/ml. Lowerconcentrations will be employed to inhibit coagulation on the graftsurface, and higher concentrations will be used where local infusion ofheparin into the blood is desired to inhibit thrombosis downstream ofthe graft, as described in Chen et al., Boundary layer infusion ofheparin prevents thrombosis and reduces neointimal hyperplasia in venouspolytetrafluoroethylene grafts without systemic anticoagulation, J.Vascular Surgery, v. 22, pp., 237-247 (1995).

[0042] The hydrogel supports the proliferation of eukaryotic cellcultures. Vascular cells such as endothelial cells, smooth muscle cells,and fibroblasts and other connective tissue cells, can thus beincorporated into the hydrogel. Human aortic endothelial cells and humandermal fibroblasts are also compatible with the hydrogels of the presentinvention. Hydrogels modified by such cell lines are, in turn,especially well adapted for implantation into the human body, and foruse as soft tissue replacement parts in the human body. Indeed,replacement parts modified by such cell lines are better able to adaptand adjust to changing physical and physiological conditions in thebody, and thereby to prevent any failure of the hydrogel which mightotherwise occur. Hydrogels modified by such cell lines are, in sum,especially well adapted for implantation in the human body, and for useas replacement parts in the human body. These cellular lines can beincorporated into the hydrogel, after it has been produced, via standardcell culture protocol generally known in the art. It is especiallyeffective to culture human aortic endothelial cells and human dermalfibroblasts using direct topical seeding and incubation in cell culturemedium.

[0043] Besides the soft tissue replacement uses set forth for thepoly(vinyl alcohol) hydrogel, discussed above, the hydrogels of thepresent invention can be used in any application in which poly(vinylalcohol) hydrogels are generally suitable, including as an MR (magneticresonance) quality control phantom, as an ultrasound or radio frequencythermal therapy transmission pad, as a substitute for an ice bag, as adenture base, and in other medical applications.

[0044] Although the following examples set out specific parameters forconstructing a PVA hydrogel in accordance with the present invention,the ordinarily skilled artisan will understand that mechanicalproperties of the PVA hydrogel may be affected by one of four factors.Those factors include: (1) weight percentage of the respectiveconstituents within the hydrogel (e.g. PVA polymer and water); (2) themolecular weight of the PVA starting material; (3) the number offreeze/thaw cycles; and (4) the duration of a freeze cycle. It is alsoimportant to note that the freeze/thaw cycle promotes an interlockingmesh or entanglement between molecules of PVA to create the mechanicalstrength. This is different than the traditional cross bits linkaccomplished by the above-referenced cross linking agents whichinevitably introduces a toxic agent into the biomaterial, thusdecreasing biocompatibility of materials which utilize those crosslinking agents.

EXAMPLE 1

[0045] A 15% by weight poly(vinyl alcohol) solution was prepared bymixing 17.6 grams of poly(vinyl alcohol) polymer (124,000-186,000 Av.MW), 99+% saponification, in 100 ml of deionized, sterile water. Themixture was placed in a loosely capped container, heated and sterilizedat 121° C. and 17 p.s.i. in an autoclave for about 15 minutes. Thecontainer was then sealed removed from the autoclave and placed under asterile ventilation hood. The mixture was then stirred to ensure ahomogenous solution. The mixture was poured into sterile syringes, beingcareful not to generate air bubbles. The poly(vinyl alcohol) solutionwas then injected upwardly into stainless steel annular molds havingstainless steel mandrels. The outer tube of the annulus had an innerdiameter of 8 mm which surrounded a 5 mm diameter mandrel. The time thatthe solution was exposed to air was minimized in order to preventevaporation of water. The mold was designed to create a poly(vinylalcohol) hydrogel with approximately a 1.5 mm wall thickness, 10 cmlong, having a 5 mm inside diameter. The mold was sealed at both endsusing O-rings and rubber caps. Air space, equaling about 8% of thevolume of the mold was deliberately maintained in order to allow forexpansion while the aqueous solution froze.

[0046] The tube was then subjected to three (3) cycles of freezing andthawing. In each of the cycles the tube was frozen by placing it uprightin a commercial freezer regulated at about −20° C., and allowing it toair cool for about 12 hours. The tube was then thawed by removing thetube from the freezer and setting it upright under ambient conditions.The tube was allowed to thaw for about 12 hours before being returned tothe freezer for another cycle.

[0047] After the mixture had been frozen and thawed three times, it wasremoved from the tube (under a sterile vacuum hood) and immersed in a 50ml, centrifuge vial containing 35 ml of deionized, sterile water. Therewas obtained a translucent to clear, gummy, weak material which wassubstantially unable to maintain its shape outside of water or otherliquid. The material was handled carefully with forceps and immersed inwater as quickly as possible. The inner diameter of the material waspreserved by keeping the inner mandrel in place. The container was thensealed and placed in a freezer at about −20° C. The mixture was kept inthe freezer for about 12 hours, and then removed and allowed to stand atroom temperature for about 12 hours. The freezing and thawing processwas repeated once, thus considering the three previous cycles within themold, the mixture was subjected to a total of five (5) cycles offreezing and thawing.

[0048] The material obtained was opaque, elastic, and non-sticky, withmechanical properties very similar to a native artery tissue. Thematerial was tested for mechanical strength according to standards ofthe Association for the Advancement of Medical Instrumentation and theAmerican National Standards Institute, published in Cardiovascularimplants—Vascular Prosthesis, ANSI/AAMI VP20-1994, section 8.3.3.3(pressurized burst strength), and Section 8.8 (suture retentionstrength). The material had a burst pressure of about 540 mm Hg.Specifically, a 6-0 suture was placed 2 mm from the edge of the graftand pulled at a rate of 150 mm/min until it pulled through the graft.The average peak pullout load for the material a suture test was about289 grams, which is greater than the pullout loads reported in theliterature for human artery and vein. Finally, the tensile modulus ofelasticity of the material was measured to be approximately 4.0×10⁵ Pa.

EXAMPLE 2

[0049] A 25.9% by weight poly(vinyl alcohol) solution was prepared bymixing poly(vinyl alcohol) polymer (124,000-186,000 Av. MW), 99+%saponification, in deionized, sterile water. As with Example 1, themixture was placed in a loosely capped container, heated, sealed removedfrom the autoclave, placed under a sterile ventilation hood, stirred toensure a homogenous solution, poured into sterile syringes, and injectedinto the molds according to the process of Example 1. In this example,however, the tube was then subjected to ten (10) cycles of freezing andthawing. The freeze/thaw cycles were similar to that of Example 1,except that the sample was allowed to cool for about 24 hours for eachfreeze/thaw cycle. The tube was then thawed by removing the tube fromthe freezer and setting it upright under ambient conditions. The tubewas allowed to thaw for about 12 hours before being returned to thefreezer for another cycle. The resulting PVA biomaterial was stiff andstrong with a burst pressure of approximately 1078 mm Hg.

EXAMPLE 3

[0050] A 15% by weight poly(vinyl alcohol) solution was prepared bymixing poly(vinyl alcohol) polymer (89,000-98,000 Av. MW), 99+%saponification, in deionized, sterile water in a manner substantiallyidentical with Example 1 except for the following differences. As withExample 1, the mixture was placed in a loosely capped container, heated,sealed removed from the autoclave, placed under a sterile ventilationhood, stirred to ensure a homogenous solution, poured into sterilesyringes, and injected into the molds according to the process ofExample 1. In this example, however, the tube was then subjected to five(5) cycles of freezing and thawing. The freeze/thaw cycles were similarto that of Example 1, in that each sample was allowed to cool for about12 hours for each freeze/thaw cycle. The resulting PVA biomaterial wassoft with a burst pressure of approximately 98 mm Hg.

EXAMPLE 4

[0051] A 25-30% by weight poly (vinyl alcohol) solution was prepared bymixing poly (vinyl alcohol) polymer (124,000-186,000 Av. MW) in sterilewater or saline (0.9% Na Cl) in a manner substantially identical withExample 1 except for the following differences. The mixture is heated at95-100° C. under atmospheric pressure to bring the mixture to a uniformfluid. This fluid is then poured into molds and frozen to −20° C. forfour hours. Next, the material is thawed to 20° C. This freeze-thawcycle is repeated until six cycles have been achieved. The material is,at least partially, removed from the mold, immersed, at least in part,and the freeze-thaw cycle is repeated until four additional cycles havebeen achieved. As an alternative to at least partially removing thematerial from the mold, the mold may be partially filled with fluidmixture, thereby allowing for expansion. The resultant PVA hydrogelconstruct is then ready for packaging and sterilization. This processyields a material having a modulus of elasticity (tensile orcompression) which is greater than 1.0 mPa. The % by weight and the MWof the PVA can be altered to provide materials with a different modulusof elasticity depending upon the particular medical application.

[0052] As demonstrated by the above-referenced examples, because the PVAhydrogel can be manufactured to be mechanically strong, or to possessvarious levels of strength among other physical properties dependingupon the weight percentage of the PVA starting material with respect toother constituents in solution, freeze time, the number of freeze/thawcycles, and the freeze temperature. As discussed above, the end producthydrogel also has a high water content which provides desirableproperties in numerous applications and which prevents the denaturing ofadditives.

[0053] The hydrogel tissue replacement construct is especially useful insurgical and other medical applications as an artificial material forreplacing and reconstructing soft tissues in humans and other mammals.Soft tissue body parts which can be replaced or reconstructed by thehydrogel include, but are not limited to, vascular grafts, heart valves,esophageal tissue, skin, corneal tissue, uretemal stents, nerve bridge,wound covering cartilage, meniscus, and tendon. The hydrogel may beformed as an implantable articulating surface for a load bearing joint,whereby the articulating surface may be fixed to bone with screws,sutures, or bioglue such as a collagenglue. Furthermore, the hydrogelmay also serve as a cartilage replacement for anatomical structuresincluding, but not limited to an ear or nose.

[0054] The inventive hydrogel may also serve as a tissue expander.Additionally, the inventive hydrogel may be suitable for an implantabledrug delivery device. In that application, the rate of drug delivery totissue will depend upon hydrogel pore size and degree of intermolecularmeshing resulting from the freeze/thaw cycles. The rate of drug deliveryincreases with the number of pores and decreases with an increasingdegree of intermolecular meshing from an increased number of freeze/thawcycles.

[0055] The hydrogel is especially suitable for vascular grafts and heartvalve replacements, because the hydrogel is thromboresistant, andbecause of the particular mechanical and physiological requirements ofvascular grafts when implanted into the body. The hydrogel may also beused for contact lenses, as a covering for wounds such as burns andabrasions, and in other applications wherein a mechanically strongmaterial is preferred.

[0056] Throughout this application, various publications are referenced.The disclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains.

[0057] The foregoing description has been presented for purposes ofillustration and description. It is not intended to be exhaustive or tolimit the invention to the precise examples or embodiments disclosed.Obvious modifications or variations are possible in light of the aboveteachings. The embodiment or embodiments discussed were chosen anddescribed to provide the best illustration of the principles of theinvention and its practical application to thereby enable one ofordinary skill in the art to utilize the invention in variousembodiments and with various modifications as are suited to theparticular use contemplated. All such modifications and variations arewithin the scope of the invention as determined by the appended claimswhen interpreted in accordance with the breadth to which they are fairlyand legally entitled.

What is claimed is:
 1. A biocompatible construct consisting essentiallyof a PVA polymer and water, said construct having the following furtherproperties: a compressive modulus of elasticity between about 0.1megaPascals and about 10 megaPascals, and a glass transition temperaturegreater than about 40 degrees C.
 2. The biocompatible construct of claim1 , said construct having the following swelling properties: thematerial dimensions of said construct change less than 20% by swellingfollowing hydration by submersion in an aqueous solution.
 3. Thebiocompatible construct of claim 2 and further defined as having itshydrated dimensions reduced by less than 20% following submersion in anaqueous solution.
 4. A biocompatible hydrogel joint resurfacing agentcomprising: a semicrystalline organic polymer; and water; said jointresurfacing agent being further defined as having the followingproperties: a water content greater than about 20%, by weight; acoefficient of friction of less than 0.1; and a compressive modulus ofelasticity of between about 0.1 megaPascals and about 10 megaPascals. 5.The biocompatible hydrogel of claim 4 , further defined as having awater content of between about 20% and about 95% by weight.
 6. A PVAconstruct consisting essentially of: a PVA polymer; and saline; saidconstruct having a compressive modulus of elasticity of between about0.5 megaPascals and about 10 megaPascals and a glass transitiontemperature greater than 40° C., said construct being further defined ashaving been prepared according to the following steps: pouring anaqueous PVA polymer mixture into a mold; freezing and thawing said PVApolymer mixture within said mold at least once to create an interlockingmesh between PVA polymer molecules to create the semicrystalline organichydrogel; allowing for expansion of said PVA hydrogel within said mold.7. A biocompatible hydrogel joint resurfacing agent comprising: asemi-crystalline organic polymer; and a water content greater than about20% by weight; said hydrogel having a compressive modulus of elasticityof between about 0.5 megaPascals and about 10 megaPascals and a glasstransition temperature greater than 40° C., said construct being furtherdefined as having been prepared according to the following steps:pouring an aqueous semi-crystalline organic polymer mixture into a mold;freezing and thawing said semi-crystalline organic polymer mixturewithin said mold at least once to create an interlocking mesh betweensemi-crystalline organic polymer molecules to create thesemi-crystalline organic polymer hydrogel; allowing for expansion ofsaid semi-crystalline organic polymer hydrogel, at least partiallywithin said mold.
 8. The biocompatible hydrogel of claim 7 which furthercontains eukaryotic cells.
 9. The PVA hydrogel of claim 8 , wherein saideukaryotic cells are selected from the group consisting of: endothelialcells, aortic endothelial cells, smooth muscle cells, fibroblasts,dermal fibroblasts, and connective tissue cells.
 10. The biocompatiblehydrogel of claim 7 which further contains radioisotopes.